The association of HLA class I heavy chains with β2-microglobulin (β2m) changes their antigenic profile. As a result, Abs react with either β2m-free or β2m-associated HLA class I heavy chains. An exception to this rule is the mAb TP25.99, which reacts with both β2m-associated and β2m-free HLA class I heavy chains. The reactivity with β2m-associated HLA class I heavy chains is mediated by a conformational determinant expressed on all HLA-A, -B, and -C Ags. This determinant has been mapped to amino acid residues 194–198 in the α3 domain. The reactivity with β2m-free HLA class I heavy chains is mediated by a linear determinant expressed on all HLA-B Ags except the HLA-B73 allospecificity and on <50% of HLA-A allospecificities. The latter determinant has been mapped to amino acid residues 239–242, 245, and 246 in the α3 domain. The conformational and the linear determinants share several structural features, but have no homology in their amino acid sequence. mAb TP25.99 represents the first example of a mAb recognizing two distinct and spatially distant determinants on a protein. The structural homology of a linear and a conformational determinant on an antigenic entity provides a molecular mechanism for the sharing of specificity by B and TCRs.
Enhancing factor (EF), a 14 kDa protein, isolated from mouse small intestines, has been reported from this laboratory. Based on our earlier studies EF has been implicated in cell proliferation. Preliminary immunohistochemical studies have shown EF to be localized in the Paneth cells of small intestines. In this paper we report the tissue distribution of EF using conditions optimized for immunohistochemical staining. In addition, the data are supported by northern blot analysis using a nick translated cDNA probe specific for EF. The results indicate that EF gene is actively transcribed mainly in the intestines. The chief source of synthesis of EF appears to be the Paneth cells located at the base of the crypts of Lieberkühn.
To establish optimized conditions for immunity against prostate cancer, we compared the efficacy of multiple approaches in autochthonous and s.c. transgenic adenocarcinoma of the mouse prostate (TRAMP)-based models. Mice immunized with interleukin (IL)-12-containing apoptotic, but not necrotic TRAMP-C2 cell-based, vaccines were resistant to TRAMP-C2 tumor challenge and re-challenge, independently of the route of vaccination (s.c. or i.p.). Administration of ;-irradiated TRAMP-C2 cells preinfected with adenovirus containing both B7-1 and IL-12 genes, unlike adenovirus containing B7-1 alone, considerably protected C57BL/6 mice from TRAMP-C2 tumor growth and extended the life span of TRAMP mice. Vaccines that included dendritic cells, instead of IL-12, were equally efficient. Whereas injections of ligandinducible caspase-1-and IL-12-containing adenoviruses cured small s.c. TRAMP-C2 tumors, nanopump-regulated delivery of viruses led to elimination of much larger tumors. The antitumor immune responses involved CD4 + -, CD8 + -, and natural killer cells and were strengthened by increasing the number of vaccinations. Intraprostatic administration of inducible caspase-1-and IL-12-containing adenoviruses resulted in local cell death and improved survival of adenocarcinoma-bearing TRAMP mice. Thus, tumor cell apoptosis induced by caspase in situ and accompanied by IL-12 is efficient against prostate cancer in a preclinical model. (Cancer Res 2005; 65(10): 4309-19)
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